A study at UCLA showed that walking increased activity in the brain and a second study from the University of Melbourne in Australia showed that walkers scored higher on cognitive tests than a control group scored.

More details about each study were published today by the Beth Israel Deaconess Medical Center.

The evidence continues to mount that challenging your brain can help to keep your memory, and probably other cognitive functions, sharp as you age. Recent study results were presented today at the American Academy of Neurology meeting in Seattle.

There is not yet compelling evidence that mental stimulation can stave off the onset of any particular disease or disorder. However, it seems more and more certain that maintaining mental fitness can keep symptoms at bay for some period of time even as some medical condition begins to interfere with normal cognitive processes.

I see a lot of news and promotion generated by companies selling computer games and work-out programs designed to optimally exercise your brain. I am hopeful that these approaches can provide true benefits and that strong scientific evidence will soon catch up and support even the boldest of these claims.

In the meantime, it is good to know that favorite hobbies, robust discussion, and reading and socializing in general all look like beneficial work outs for the brain.

Of specific importance, I think the closing point about symptoms associated with abnormal thyroid function should be noted. Thyroid disorders are fairly common, can produce a host of worrisome symptoms including memory loss, and are generally treated with success.

Contributed by: Michael Rafii, M.D., Ph.D - Director of the Memory Disorders Clinic at the University of California, San Diego.___________________________________________

This is the third blog in my series about the causes of AD.

While the Amyloid hypothesis has been in favor in recent years, buildup of amyloid plaques does not correlate well with the loss of brain cells. As such, scientists have restlessly searched for alternative explanations.

One such explanation is the tau hypothesis, encompassing the idea that tau protein abnormalities initiate the disease cascade. According to this theory tau proteins pair with other threads of tau and form damaging tangles inside nerve cells. When this occurs, the cell's transport systems disintegrate and malfunction which may disrupt communications between cells and later cause cell death.

As we know, exercise, diet, OTC supplements, intellectual stimulation, social activity, and care giver education have all been shown to have benefits on the overall health of Alzheimer's patients.

A new study out of Oxford now shows that, when evaluating the impact of certain drugs, delivery method is also an important variable. In this study, delivery through a skin patch allowed for smaller doses to deliver the same impact on cognition with fewer side effect.

Contributed by: Michael Rafii, M.D., Ph.D - Director of the Memory Disorders Clinic at the University of California, San Diego.___________________________________________

This is the second blog in my series about causes of AD.

Among many theories about the complex cause of Alzheimer’s disease, the amyloid hypothesis is currently driving the most drug development. The amyloid hypothesis states that a buildup of deposits (amyloid) is the fundamental cause of Alzheimer’s disease. It is a compelling theory because a gene associated with this form of amyloid is located on chromosome 21 and people with an extra copy of this gene (those with Down Syndrome) almost universally exhibit AD by 40 years of age.

Also, APOE4, the major genetic risk factor for AD, leads to excess amyloid buildup in the brain before AD symptoms arise. Thus, amyloid buildup precedes clinical AD. Further evidence comes from the finding that mice with a mutant form of the human genes associated with amyloid develop Alzheimer's-like brain pathology.

Evidence that potentially weakens this theory is that an experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia.

Contributed by: Murali Doraiswamy, M.D., Professor of Psychiatry at the Duke University Medical Center, and author of The Alzheimer's Action Plan.___________________________________________

The results of another study on the association between non-steroidal anti-inflammatory drugs (NSAIDs) and the risk for dementia were in the headlines this week.

This study, which tracked nearly 3,000 subjects for a twelve year period, did not show any reduction in the prevalence of dementia among NSAID users. To the contrary, the results suggested a possible increase in cognitive decline among these subjects.

NSAIDs, known in common forms as naproxen and ibuprofen, have been associated with lower risk of dementia according to many earlier news headlines but not necessarily by the bulk of earlier research results. While several individual studies have reached conclusions in one direction or another, the full body of research in this field is still quite mixed.

At this point, there is still a significant gap in our understanding of how inflammation may or may not be related to dementia. As I noted in the USA Today, these latest results are not at all surprising to me and highlight our need for deeper knowledge in this area.

Contributed by: David Geldmacher, M.D., Medical Director of the Memory Disorders Clinic at the University of Virginia.___________________________________________

The news is inThe latest Cochrane Review on the role of statin drugs states that they do not lower the risk of dementia.

These findings come primarily from the results of two prospective randomized trials involving over 26,000 subjects. Neither clinical impressions nor neuropsychological tests revealed any reduced dementia risk over three to five years of treatment. The average LDL cholesterol level at study entry was about 135 mg/dl, which is within the current indication for treatment, but not by a lot.

For better or worse?Statin treatment was also not associated with worsened cognition, but the size of these studies would prevent rare but meaningful cases of from showing up in the statistical outcomes. See here for an example of what can go wrong in statin use.

So, why is this news? Many reports, including one from the well-respected Rotterdam Study earlier this year, suggest that statins, but not other cholesterol lowering agents, have a substantial effect on lowering dementia risk.

Apples and OrangesThe Cochrane Review identifies “indication bias” as a likely contributor to the differences between prior observational studies and the randomized trials. I agree.

Since most statin prescriptions were written for much higher levels of total and LDL cholesterol when data was collected for the observational studies, the "indication" for treatment probably differed between the old studies and the new ones. The differing outcomes may therefore simply represent the result of an apples-and-oranges comparison beween the effects of statin use in people with cholesterol levels high enough to warrant prescription drug treatment and others with cholesterol levels low enough that placebo use wasn't considered dangerous.

If you’re having a sense of déjà vu about this mismatch, we’ve seen much the same story with hormone replacement therapy and dementia risk. See here for more of my thoughts on that can of worms.

Contributed by: Michael Rafii, M.D., Ph.D - Director of the Memory Disorders Clinic at the University of California, San Diego.___________________________________________

Alzheimer’s disease is very complex and remains poorly understood at the pathological level. Several theories have emerged over the course of research in this field.

In the next series of blogs, I will describe these three prevailing theories of how scientists believe AD develops.

The oldest theory is the Cholinergic hypothesis, which proposes that AD is caused by reduced function of a certain chemical in the brain called acetylcholine. The chemical is known to be important in memory formation and brains of patients with AD have less acetylcholine. In fact, most medications currently approved for AD act by increasing acetylcholine levels in the brain. However, their ability to treat the disease has been limited, indicating other factors at play.

It is now thought that the acetylcholine deficiency plays a contributing role in the development of AD, but it is not likely to be the central cause.

Contributed by: Michael Rafii, M.D., Ph.D - Director of the Memory Disorders Clinic at the University of California, San Diego.___________________________________________One of the mysteries of AD has been the normal function of the amyloid precursor protein (APP) which is concentrated at the synapse. Even though the amyloid plaques which have been viewed as a hallmark sign of AD result from APP, it seems unlikely that AD is simply a buildup of misprocessed APP . In a recent study, scientists from the Buck Institute and the CNRS (Centre Nationale de la Recherche Scientifique) show that APP binds to netrin-1, a protein that helps to guide axons.

When netrin-1 was given to mice that have a genetic mutation for Alzheimer’s disease, their symptoms were reversed. These results suggest that the long-held belief that AD is caused by neuronal damage inflicted by the amyloid plaques may be wrong; instead, it is beginning to appear that the disease stems from an imbalance between the normal making and breaking of synapses in the brain, with netrin-1 supporting synapse formation and the APP causing breaking the connections.

In their research, not only did the netrin-1 binding to APP keep the neurons alive and connected, but it also downregulated the production APP itself.

The fastest path to better treatment for AD is to start diagnosing the disease at an earlier stage and intervening while the brain is still somewhat healthy. On average, we currently diagnose AD about 8-10 years after the onset of symptoms when the pathology is in the end stages and massive brain damage has already occurred. The current drugs may not cure the disease but they can delay progression meaningfully if patients get access to them as soon as symptoms manifest.

Solution: Patients and primary care physicians must engage in proactive dialogue about cognitive health and be vigilant toward investigating suspicion or evidence of memory decline.

Alzheimer's disease appears to slowly damage the brain for many years prior to the appearance of clear symptoms. As such, we generally do not detect and diagnose AD until irreversible brain damage has occurred and memory loss and/or behavioral disturbances are pronounced. At that point, the extent of the underlying damage is severe and a return to full cognitive function is unlikely if not impossible.

With this view, we know that the best opportunity to intervene meaningfully is during the period prior to the manifestation of clear symptoms. To do so, we must improve our ability to evaluate early stage risks and to objectively identify subtly abnormal cognitive function at the individual level.

In recent months, experts in the fields of epidemiology, risk assessment, cognitive evaluation, imaging, and biomarker development have convened under the auspices of the National Alzheimer's Association to discuss a framework for improving early risk assessment. An overview of their discussions is published in the current issue of Alzheimer's and Dementia: Early Risk Assessment for Alzheimer's Disease. In this article, lead author Maria Carillo clearly outlines the state of the field and identifies those questions most germane to future progress.

New potential treatments for Alzheimer's disease and the progress of their FDA trials are high interest news stories with lots of coverage. Two Dimebon studies are currently in progress or being planned. For those interested in learning more about how to participate in one of these studies, detail links are below.

The selection criteria and additional details for the CONNECTION study are published at the Medivation website.

Information about the forthcoming CONCERT study, a combination therapy approach including Aricept, is available at a special "CONCERT study" website where information will be published as it becomes available.

Contributed by: Michael Rafii, M.D., Ph.D - Director of the Memory Disorders Clinic at the University of California, San Diego.___________________________________________Dimebon may soon become the next medication approved for AD. In my last blog, I described the long and arduous path taken by any new compound until it reaches patients. It looks like Dimebon is advancing down this road quite nicely. Pfizer, and its partner Medivation just announced initiation of a 12-month, Phase 3 clinical trial called CONCERT, which evaluates Dimebon plus Aricept for AD. Dimebon is thought to protect mitochondria of neurons damaged by AD, whereas Aricept works by boosting the cholinergic system, which is injured in AD.

What's interesting is that this Phase 3 program also includes the confirmatory 6-month CONNECTION study, which builds on results of the first pivotal trial of Dimebon alone and is the last step needed for FDA approval of Dimebon as monotherapy for AD.

Results of the first pivotal clinical trial of Dimebon in Alzheimer’s disease, published in the July 19, 2008 issue of The Lancet, showed that Dimebon improved the clinical course of Alzheimer’s disease. In this randomized, double-blind, placebo-controlled trial of 183 patients with mild-to-moderate Alzheimer’s disease, patients treated with Dimebon experienced statistically significant improvements compared to placebo in all the key aspects of the disease: memory and thinking, activities of daily living, behavior and overall function. After both six months and a full year of treatment, Dimebon-treated patients were significantly better than placebo-treated patients on all key aspects of the disease.

In January 2008, the FDA stated that only one more pivotal study is required to support the approval of Dimebon as monotherapy for AD. If the results are successful, as deemed by the FDA, neurologists will have one more option in their armamentarium for treating AD.

Contributed by: Dennis Fortier, President, Medical Care Corporation________________________________________________A while back, I posted some general information under the heading of Dementia 101. It was top level information designed to clarify the definition of the term and to point out how it is often confused with various diseases that cause dementia.

Today, I received an article that goes deeper in explaining some of those causes in more detail. It seems like the logical next step in understanding this topic and I encourage any interested readers to have a look. The article, Understanding Dementia, is written by gerontologist Denise Talbot.

Contributed by: Dennis Fortier, President, Medical Care Corporation________________________________________________A fair amount of research has been completed showing conclusively that psycho-social intervention and an educated caregiver can improve the overall well being of an Alzheimer's patient. I plan to review some of that research in coming posts.

In the meantime, it is clear that many caregivers are at their breaking points and stretched to the limit with the burden of caring for a loved one with Alzheimer's disease. There are many informational resources aimed at helping these people but it is hard to imagine when they would have time to go online ad read them.

Contributed by: Dennis Fortier, President, Medical Care Corporation________________________________________________As I noted here last week, an educational campaign sponsored by the Alzheimer's Society seemed to be sensitizing the public to the importance of seeking medical attention to discuss memory concerns. This comment was based on a survey of people in the UK who reported that their likelihood of seeing a physician about a memory concern was increased after seeing the advertising campaign.

In news today, physicians have reported an actual increase in the number of patients coming to them with suspicion of a memory disorder. This provides encouraging further evidence that the campaign will have a meaningful impact on the health of the UK's aging population.

As earlier facts presented in this blog make clear, educating the public and catalyzing earlier intervention against memory impairing medical conditions looks to be one of the most effective strategies in combating the growing prevalence of dementia. I hope we can all support and implement a similar approach in the USA.

Current treatments do not cure AD but they can slow disease progression. This is an important difference. If you are expecting treatment to help the patient regain their former cognitive abilities, you will almost surely be disappointed. If you are expecting some stabilization or slowing of their decline, you may well be satisfied.

Remember: Slowing the advance of the disease can add precious months or even years to a patient’s independence and should not be marginalized as meaningless simply because a cure would be better.

While I heartily agree with the need to identify and publish standards of care in this field and I applaud the author (Diana Kerwin, MD) for her efforts, this article blurs the important differences between Mild Cognitive Impairment, Dementia, and Alzheimer's Disease. Helping the public to clearly differentiate and fully understand these terms, (as Dr. Kerwin surely does) is one of the main purposes of this blog.

Based on the title of the article, these are best practices for detecting early Alzheimer's disease. Theoretically, this could mean detection in a pre-symptomatic stage or a bit later when the disease has progressed to the MCI stage. However, when detection occurs later than the MCI stage, we are really no longer discussing early stage Alzheimer's but rather mid to late stage Alzheimer's disease. The confusion comes from the fact that mid to late stage Alzheimer's often causes early stage dementia. The terms "Alzheimer's" and "Dementia" are distinct and cannot be (should not be) carelessly interchanged.

On average, Alzheimer's disease begins with a seven year period of mild symptoms prior to a patient becoming demented. As such, mid to late stage Alzheimer's is usually contemporaneous with early stage dementia. Switching carelessly between the terms breeds unnecessary confusion.

As a final note, the author also included a list of "optimal screening tests and tools to prevent delayed diagnosis of mild-to-moderate dementia patients" which I contend perpetrates somewhat of a false frame. Patients who are mild to moderately demented have a cognitive deficit severe enough so as to be obvious to a caregiver or physician. These patients can no longer care for themselves and no screening tests or tools are necessary to detect the problem. Truly beneficial tests and tools are those that distinguish more subtle impairment from normal declines due to healthy aging.

Contributed by: Dennis Fortier, President, Medical Care Corporation_________________________________________________________One of the major challenges in the fight against memory disorders is the general lack of understanding about the importance of early intervention. While we have all come to accept the importance of a timely diagnosis in the case of cancer and other progressive diseases, we have not, as a society, made that connection to Alzheimer's disease.

I am very encouraged to read today about a campaign funded by the Alzheimer's Society in the UK that has reportedly been quite successful in this regard. Apparently, the educational campaign (Titled: Worried About Your Memory?) has increased the likelihood that a person with a memory concern will discuss their situation with a physician. This is an important step that we need to encourage in the USA as well.

There has been a lot of press recently about diagnostic tests for Alzheimer's disease including this piece from Examiner.com that has garnered a lot of attention today. Digesting this news requires a broad perspective on the problem.

Physicians will tell you that solving a medical problem involves three distinct steps:

First you need to recognize that a problem exists. This is often a simple task when clear symptoms are present. Other times however, symptoms are vague and a physician must take steps to determine whether or not a legitimate health concern is at hand.

Second, you must diagnose the problem. If the symptom is blurry vision, for example, the physician must diagnose the root cause of the problem because a care plan for diabetes is much different then a care plan for a scratched cornea.

Third, the physician must select the appropriate care plan and oversee its administration.

When all three steps have clear guidelines that lead to successful clinical outcomes, physicians generally deliver fantastic medical care. When one or more of these three steps is uncertain, standards of care tend to vary from good to less good. In the case of Alzheimer's disease, it turns out that all three steps have some uncertainty.

Early stage Alzheimer's disease has generally vague symptoms usually including subtle memory loss. This is challenging for physicians because many adults, a large percentage of whom are perfectly healthy, sense that their memory is not as sharp as it may have been in the past. The difficulty in sorting the healthy from the unhealthy leads to a delay in meaningful intervention.

Once a physician decides a problem is present, the diagnostic process for AD is perceived as uncertain based on the over-emphasized fact that autopsy is the only certain approach. Importantly, any physician following the NINDS-ADRDA diagnostic guidelines can accurately diagnose AD and other problems on a consistent basis (but this is not well understood by most primary care physicians). Finally, current treatment options are considered uncertain given the variability with which patients respond. Some patients seem to respond while others do not. Overall, there is a lot of uncertainty around this disease.

The primary point of this post is that stories like the one referenced above can only be appreciated in the context of the full continuum of clinical steps to identify, diagnose, and treat Alzheimer's disease. While an accurate diagnostic test will be a welcomed advance, the problem is quite complex and such a test will have limited impact until we can sure up all three steps in the care process.

Contributed by: Michael Rafii, M.D., Ph.D - Director of the Memory Disorders Clinic at the University of California, San Diego.___________________________________________

Before a drug can be approved for use by patients, there is a set of clinical tests that must be performed. There is the Pre-Clinical Research Stage. Here the drug is synthesized and purified. Animal tests are performed, and institutional review boards assess the studies and make recommendations on how to proceed. If the recommendations are positive, then an application to the FDA occurs and clinical tests in humans may begin.

Phase 1: Clinical studies in this phase represent the first time that an Investigational New Drug (IND) is tested on humans, either healthy volunteers or patients. The purpose of these studies is to look at the metabolism and any potential side effects of the drug in humans. Phase 1 studies are usually conducted on 20 to 80 subjects and are therefore concerned with safety and tolerability.

Phase 2: The purpose of phase 2 is to determine the efficacy of a drug to treat patients with a specific disease or condition, as well as learn about common short-term side effects or risks. These studies are conducted on a larger scale than phase 1 studies and typically involve several hundred patients.

Phase 3: These trials provide even more information about the effects and safety of the drug, and more importantly assess the efficacy or the drugs ability to treat the disease. Phase 3 studies generally involve several hundred to several thousand people and can last from months to a couple of years. These trials are almost always double-blind and placebo controlled. This means that neither the subjects nor the researchers know who is getting the investigational drug versus placebo (or sugar pill).

There are several checks and balances in the process of clinical trials; among them is the use of institutional review boards (IRBs) and advisory committees. IRBs are designed to protect the rights and welfare of people participating in clinical trials both before and during the trials. IRB's are made up of a group of at least five experts and lay people with diverse backgrounds to provide a complete review of clinical proceedings. Also, clinical trials are monitored for their entire duration by study monitors and safety monitoring boards that follow subjects in real time as trials progress.

The Application Process:Once a trial is complete, or closed, the data is then analyzed by statisticians and researchers to look for efficacy. Since many trials are multi-center, this process can take many months, the results of which are eventually submitted in a formal application to the FDA for final approval. This New Drug Application (NDA) must include results and analyses from tests of the drug on both animals and humans. The NDA must provide enough detailed information for FDA reviewers to make several critical decisions. The result of the study must show whether the drug is safe and effective and whether its benefits outweigh its risks.

The process of developing and testing a new drug is a lengthy one. The FDA estimates that it takes a little over 8 years to test a drug, including early laboratory and animal testing, before there is final approval for use by patients.

FDA Approval The FDA's decision whether to approve a new drug for marketing comes down to answering two questions: 1. Do the results of blinded, placebo-controlled studies provide substantial evidence of its effectiveness? 2. Do the results show that the product is safe under the explicit conditions of use in the proposed labeling? Here "safe" is a relative term; it means that the benefits of the drug appear to outweigh its risks. When the review is complete, the FDA writes to the applicant to say the drug is either approved for marketing, is "approvable," provided minor changes are made, or is not approvable because of major problems.

The March 27 issue of Alzheimer's & Dementia, the journal of the National Alzheimer's Association, is dedicated to the notion of preventing Alzheimer's disease. In a tone-setting editorial (Prevent Alzheimer's disease by 2020: A national strategic goal), authors Zaven S. Khachaturian and Ara S. Khachaturian outline a road map to achieve this important national goal.

While the looming specter of rising dementia prevalence is daunting, it is clear that coordination of resources and well-directed funding could catalyze a more efficient discovery process and accelerate advances in this field. Success will require resources, infrastructure, and central governance of a process that integrates several legacy research efforts currently underway. The author's vision is broad but tangible, comparing the goal of preventing this disease in the next decade to a similarly spectacular scientific feat accomplished by an earlier generation that put a man on the moon with the Apollo Space program.

Overall, it is an article that breeds hope through its comprehensive consideration of both the problem and the solution. Several, more focused perspectives are offered by luminaries in the field with insight on some specific element of this multi-faceted problem. Taken together in the full issue, these perspectives paint a clear and plausible picture of how we can indeed, prevent Alzheimer's disease by 2020.